Natural scaffolds-inspired synthesis of CF3-substituted macrolides enabled by Rh-catalyzed C-H alkylation macrocyclization

The development of innovative strategies and methods to provide natural product-like macrocycles not accessible by biosynthesis, but endowed with novel bioactivities and simplified structure, is highly desirable. Inspired by the key scaffolds of rapamycin and FR252921, herein, we report a Rh(III)-catalyzed C-H alkylation macrocyclization, which enables access to CF3-substituted macrolides. DFT calculations reveal that the chemoselectivity between C-H alkylation and olefination macrocyclization was highly controllable. Moreover, the unique CF3-substituted macrolides showed potent anti-inflammation activities against TNF-alpha, IL-6 and CCL2 mRNA expression. (C) 2021 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Automated summary

A Rh(III)-catalyzed C-H alkylation macrocyclization was developed to access CF3-substituted macrolides with novel bioactivities. The chemoselectivity between C-H alkylation and olefination macrocyclization was controllable, and the CF3-substituted macrolides exhibited potent anti-inflammation activities against TNF-alpha, IL-6 and CCL2 mRNA expression.